It is first proposed by Mosmann et al. that Lymphocytes, called helper T cells which play the central role in immune responses are classified into two subsets. They classified mouse helper T cells (Th) into Th1 and Th2 depending on the kinds of cytokines produced (J. Immunol. 136, 2348-2357 (1986)).
As Th1-type cytokines, interleukin 2 (IL-2), interferon γ (IFN-γ), etc. are illustrated. As Th2-type cytokines, interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 13 (IL-13), etc. are illustrated.
Nowadays thinking of the classification into Th1/Th2 is applied to the classification of helper T cell subsets, and also regarding a variety of immune responses in the living body on the point of view of which subset of helper T cells mainly participates, the immune responses have become to be interpreted “immune responses on Th1-type” or “immune responses on Th2-type”, respectively.
Immune responses on Th1-type are mainly induced by cytokines such as interleukin 2 (IL-2), interferon γ (IFN-γ), etc. produced by activated Th1. Thus, it is known that Th1 cytokines participate to cell-mediated immunity such as protection mainly against infections of virus, bacteria, etc. by activation of macrophage, natural killer cells etc., or by further activation of Th1 via IL-12 etc. produced by the activated macrophages.
On the other hand, immune responses on Th2-type are mainly induced by cytokines such as IL-4, IL-5, etc. produced by activated Th2. Thus, it is known that Th2 cytokines participate to humoral immunity such as production of antibodies (e.g. IgE class) from B cells.
Since Th2 produce cytokines such as IL-4 or IL-5 which relates to allergic reaction, as mentioned below, Th2 are suggested to be the responsible cells on allergic reaction. For example, IL-4, a typical Th2-type cytokine, induces production of IgE antibodies from B cells. IL-4 also induces expression of VCAM-1 gene, which is an important molecule which works when eosinophils adhere to vascular endothelial cells and infiltrate into the tissue (Farumashia, 29, 1123-1128(1993)). Recently IL-4 has been paid attention as a differentiation-inducing factor for Th2. IL-5, another Th2-type cytokine, induces differentiation, migration and activation of eosinophils. Allergic inflammation is characterized in being triggered off by infiltration, activation and degranulation of eosinophils, as typical chronic airway inflammation in asthma. Thus IL-5 is considered to be a factor inducing allergic inflammation.
Since Th2 cytokines have above properties, it is recognized that Th2 control both allergic reactions of “early phase reaction” by IgE antibodies or mast cells and “late phase reaction” by eosinophils, and therefore, Th2 are central cells in allergic inflammation. And it is considered that allergic diseases are caused by over expression of Th2-type immune responses. This consideration is also supported by findings of presence of Th2 or production of Th2-type cytokines such as IL-4, IL-5, etc. in the lesion of allergic disease, such as airway or skin.
Therefore, it is considered to be important to suppress immune responses of Th2, in order to inhibit both early phase and late phase reactions, or inhibit allergic inflammatory reaction characterized with infiltration and activation of eosinophils in the stage of fundamental source and to treat therapeutically and prophylactically general allergic diseases. Namely, if a drug is developed to suppress immune responses of Th2-type, the drug will be one for therapeutic and prophylactic agent for allergic diseases.
In especially serious chronic asthma or atopic dermatitis among allergic diseases, late phase reaction is considered to play an important role. However, anti-allergic agents used nowadays are mainly based on anti-histamine activity and inhibit only early phase reaction and clinical effect thereof is not satisfactory. From such viewpoints too, it has been desired to develop the drug which inhibits both early phase and late phase reactions by suppressing immune responses of Th2 and treats therapeutically and prophylactically for general allergic diseases as mentioned above.
Moreover, bronchodilators, which are represented by xanthine derivatives or β-stimulants which have been used as asthma agents for long years, are known to have suppressive activity of constriction of broncho smooth muscle by various stimulation. However, these are ineffective to chronic airway inflammation which is a basic cause for asthma. In addition, side effects of xanthine derivatives or β-stimulants to circulatory organs are anxious. In recent asthma therapy, as definitely shown in the guide line of WHO, asthma is taken as chronic inflammation of airway and it has made a principal object to cure the chronic inflammation of air way. The chronic inflammation of airway in asthma is triggered off by infiltration, activation and degranulation of eosinophils and has its pathologic characteristic feature which results in hypertrophy and fibrillation of airway-epithelium. According to the above guide line, the sole steroid inhalants effective to the chronic air way inflammation are now positioned as the first chosen medicine to asthma of more than middle degree.
As a result, steroids have been often used for serious asthma and atopic dermatitis as being considered as the sole effective drugs. However, it becomes problem that by using such steroids for long terms various side effects (steroid dermatitis, induced infected disease, discorticism, etc.) occur.
From the point of these views too, it has been desired to develop the drug which selectively suppresses immune responses on Th2 and inhibits both early phase and late phase reactions, or inhibits allergic inflammatory reaction characterized with infiltration and activation of eosinophils in the stage of fundamental source and is therapeutically and prophylactically effective for general allergic diseases.
Furthermore, when it is planned to develop the therapeutic or prophylactic drugs which have less side effects, it seems that the drugs which suppress immune responses on Th2 as mentioned above and enhance immune responses on Th1 simultaneously, are more preferable as medicines. As mentioned above, since Th1 play an important role for the living body, namely infection-protection against virus and bacteria by mainly producing IFN-γ, the drugs which suppress the immune responses on Th2 and enhance activity of Th1 are very preferable in view of side-effects. For example, immunosuppressives, e.g. cyclosporin or FK506 are known to strongly inhibit activation of Th2. However, both cyclosporin and FK506 show non-specific suppression against immune responses, namely not only inhibit activation of Th2, but also more strongly inhibit activation of Th1. Therefore, serious side effects such as opportunistic infection or increase of carcinogenic rate caused by such non-specific suppression against immune responses have been problem. Other non-specific immunosuppressives are also considered to have same problems.
As mentioned above, the drug which enhances immune responses on Th1 represented by production of IFN-γ and suppresses immune responses on Th2 represented by production of IL-4 and IL-5 simultaneously, will be a therapeutic and prophylactic agent for allergic diseases with less side effects.
Autoimmune diseases in the state that production of an antibody or humoral immunity are abnormally enhanced, such as systemic lupus erythematosus are also considered to be in the state that immune responses of Th2 are abnormally enhanced (Medical Immunology 15, 401 (1988)). Therefore, the drug which enhances immune responses of Th1 and suppresses immune responses of Th2 is expected to become a therapeutic agent for autoimmune diseases.
Pyrimidine derivatives having general anti-virus activity are disclosed in Japanese Patent Publication A 9-301958 and Japanese Patent Publication A8-134044. However, there is no suggestion of pyrimidine derivatives of the present invention which enhances immune responses of Th1 and suppress immune responses of Th2.